John Svaren, PhD

Position title: Professor, Comparative Biosciences

John Svaren, PhD

PhD, Vanderbilt University
Director, IDD Models Core

Contact Information

Waisman Center
Room 659
1500 Highland Avenue
Madison, WI 53705
Lab Website: Svaren Lab Home Page
School of Veterinary Medicine

Research Statement

The myelin sheath that insulates peripheral nerve fibers is critical for efficient conduction of nerve signals through motor and sensory nerves. Myelin is produced by Schwann cells in a developmental process that is triggered by their association with developing axons. Some peripheral neuropathiesincluding Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN)are caused by deficits in myelin formation and maintenance by Schwann cells. Most of the genetic causes of these peripheral neuropathies have been traced to mutations in genes coding for myelin-associated proteins (e.g. myelin protein zero). However, mutations in the gene coding for the EGR2 transactivator have recently been associated with these diseases, confirming previous work showing that the EGR2/Krox-20 is a critical regulator of myelin formation in mouse development. The identification of a critical transcriptional activator in the myelination process has allowed us an opportunity to understand how coordinated regulation of many genes contributes to the myelination process.

Our research goal is to elucidate the mechanisms of transcriptional control that become altered in peripheral nerve diseases associated with EGR2 mutations. Several neuropathy-associated mutations inhibit DNA-binding by EGR2, but all of these mutations are dominant. This finding is surprising since only one functional allele of EGR2/Krox-20 is sufficient for myelin formation in mice. The evidence suggests that the dominant mutants effectively sequester a critical cofactor of EGR2 activity, and studies of protein-protein interactions have suggested that interaction with another regulator, Sox10, is critically involved. Finally, one of the EGR2 mutations alters a domain that interacts with the NAB family of corepressor/coactivator proteins. This recessive mutation therefore strongly implicates the NAB proteins as important regulators of myelination. Therefore, we are also focusing on the use of both gene microarrays and quantitative PCR assays to try to understand how EGR2 and NAB proteins regulate a gene network that controls myelination of peripheral nerves by Schwann cells.

The spectrum of peripheral myelinopathies (including CMT, DSS, and CHN) cause a variety of clinical problems and the more severe cases often result in premature death due to decreased respiratory function. However, there is great promise for therapies that treat this type of disease since the affected Schwann cells remain viable during the course of the disease. Even in more severe cases, the normal time of myelin formation (during the first year of life) should allow restorative therapy in those cases where a specific genetic cause is identified. Other types of therapy based on rapidly developing stem cell technologies are also strong possibilities. Because EGR2 coordinates gene regulation events that are vital for proper myelination of peripheral nerves, development of any of these therapies will clearly benefit from elucidation of the genetic program controlled by EGR2 and NAB proteins.

Selected Publications